A divergent and selective synthesis of ortho- and para-quinones from phenols

Article abstract of DOI:10.1016/j.tet.2015.04.095

Abstract We describe a divergent synthesis of substituted ortho- and para-quinones by catalytic aerobic oxygenation of phenols. Substituted quinones are omnipresent in chemistry and biology, but their synthesis frequently suffers from low efficiency and poor scope. Our methodology employs a catalytic aerobic di-functionalization of phenols to aryloxy-ortho-quinones. Regioselective substitution with an alcohol provides the alkoxy substituted ortho- or para-quinone, while hydrolysis affords the para-hydroxyquinone. These are mild and selective conditions for the synthesis of diversely substituted quinones from readily available phenol starting materials.

Full text of DOI:10.1016/j.tet.2015.04.095

Tetrahedron xxx (2015) 1e15
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A divergent and selective synthesis of ortho- and para-quinones
from phenols
*
Zheng Huang, Ohhyeon Kwon, Kenneth Virgel N. Esguerra, Jean-Philip Lumb
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a divergent synthesis of substituted ortho- and para-quinones by catalytic aerobic
oxygenation of phenols. Substituted quinones are omnipresent in chemistry and biology, but their
synthesis frequently suffers from low efficiency and poor scope. Our methodology employs a catalytic
aerobic di-functionalization of phenols to aryloxy-ortho-quinones. Regioselective substitution with an
alcohol provides the alkoxy substituted ortho- or para-quinone, while hydrolysis affords the para-hy-
droxyquinone. These are mild and selective conditions for the synthesis of diversely substituted quinones
from readily available phenol starting materials.
Received 24 March 2015
Received in revised form 23 April 2015
Accepted 24 April 2015
Available online xxx
Keywords:
Phenol
CeH oxidation
Quinone
Ó 2015 Elsevier Ltd. All rights reserved.
Aerobic catalysis
Copper
Estrone
1. Introduction
ortho-quinones (5a, 2a, and 2b) as biomimetic organocatalysts,
which display complementary selectivity in the aerobic oxidation
ortho- and para-Quinones are fundamentally important to bio-
chemical processes that include cellular respiration, melanogene-
sis, and blood coagulation.1,2 They possess unique photo-physical
properties and are important chromophores in natural and syn-
thetic dyes.3 They are a common pharmacophore in natural prod-
ucts,4 and are of interest to the pharmaceutical industry.5 They are
also redox active, making them important components of enzy-
matic processes6 and bio-mimetic catalysts.7 Their reactivity can be
finely tuned by substituents on the quinoidal ring, while their ar-
rangement as either ortho- or para-isomer can have a dramatic
impact on their overall physical properties.8
An important sub-class of ortho- and para-quinones are those
which bear oxygen substituents (Fig. 1a).1b,4c,9 Biologically active
examples include the tanshinone quinones (cryptotanshinone and
tanshinone IIA), which are prevalent in traditional Chinese medi-
cine.10 Coenzyme Q10 is a facilitator of electron transport in the
mitochondria,2e,11 and atovaquinone (Mepron) is used for the
treatment of pneumocystis pneumonia.12 Examples of alkoxy-
quinones in enzymatic catalysis are well-known, and include
topaquinone in the active site of amine oxidase.13 The mechanism
of amine oxidase has inspired Stahl and Luo to develop para- and
of amines (Fig. 1b).8,13b,14 Finally, quinones are important in-
termediates for synthesis,1b,9,15 as exemplified by the hetero-[4þ2]
cycloaddition of benzyloxy-ortho-quinone 6, which created the
unique macrocycle of sporolide B in Nicolau’s classic total synthesis
(Fig. 1c).16
In spite of their widespread occurrence, quinones can be diffi-
cult to prepare since they are redox active, electrophilic, and good
ligands for a range of transition metals.17 Their synthesis from
phenol, catechol or resorcinol derivatives requires CeH oxygena-
tion as well as de-aromatization. This is possible with a range of
oxidants, although yields, selectivity, and scope are limited
(Scheme 1a).13b,18 Milder and higher-yielding oxidations occur for
hydroxyquinols, but the synthesis of differentially protected poly-
phenols can require intricate protecting group manipulations.16,19
Thus, the more facile oxidation of an oxygenated starting material
can be offset by the difficulty of its synthesis.
In considering these challenges, we were drawn to a synthesis
of alkoxyquinones reported by Maumy,20 in which oxygenative
coupling of 4-methoxy-phenol (4l) and substitution of the
resulting ortho-quinone 1h with an alcohol afforded
di-alkoxyquinones (Scheme 1b). While the methodology was only
demonstrated with 1h, it demonstrated that an isohypsic sub-
stitution could introduce a range of oxygen nucleophiles under
relatively mild conditions. We reasoned that this synthesis could
be developed into a general methodology, with the potential to
* Corresponding author. Tel.: þ1514 398 4889; e-mail address: jean-philip.lumb@
mcgill.ca (J.-P. Lumb).
http://dx.doi.org/10.1016/j.tet.2015.04.095
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
Fig. 1. Important ortho- and para-alkoxyquinones and para-hydroxyquinones in biology and chemistry.
access either ortho- or para-isomer directly from phenols under
mild conditions (Scheme 2). Our strategy relies on a catalytic
aerobic alternative to Maumy’s stoichiometric oxygenative cou-
pling, which we reported recently.21 Based on Maumy’s pre-
cedent, we expected that a substitution of 1a with alcohols under
basic conditions would provide 4-alkoxy-ortho-quinones, where
diversity at R1 would be derived from readily available phenol
starting materials. Under acidic conditions, we suspected that
substitution would provide the thermodynamically favored para-
isomer, affording either configuration of the quinone in a two-step
process from the phenol.
the substitution is sensitive to the choice of solvent, and an 83%
yield of 3a was obtained using dichloromethane (CH2Cl2) at 0.5 M
relative to 1a (entry 8). Selectivity improved when triflic acid (TfOH,
pKa ꢀ12) was used as the catalyst, although both TfOH and TsOH
were used when evaluating substrate scope (vide infra). With both
of these acids, para-quinone 3a is the only observed product,
whereas camphor sulfonic acid (CSA, pKa 1.2) affords a mixture of
2a and 3a at incomplete conversion. A cursory screen of Lewis
acidic metals (entries 15e18) returned variable results, none of
which improved upon those obtained with the sulfonic acids.
Our optimized conditions for the synthesis of ortho- and para-
quinones remain effective across a range of alcohols, but display
different substituent constraints (Table 2). Whereas substitution
under acidic conditions tolerates sterically encumbered 2ꢁ alcohols
(3ge3j), decreases to both rate and efficiency are observed under
basic conditions (2ge2j). For secondary alcohols, 20 mol % DBU is
required, and with the exception of MeOH, complete conversion
requires 12 h. Under acidic conditions, the electronic nature of the
alcohol dominates reactivity, and decreases in efficiency are ob-
served for electron deficient 1ꢁ alcohols (3d, 3f). These trends are
consistent with a mechanism of substitution that involves a tetra-
2. Results and discussionL
As a point of departure, we revisited Maumy’s conditions20 for
alcohol substitution using model quinone 1a, catalytic quantities of
base and methanol (MeOH) (Table 1). Using 10 mol % of 1,8-
diazobicyclo[5.4.0]undec-7-ene (DBU), the substitution was opti-
mized to a 94% yield of 2a when tetrahydrofuran (THF) was used as
the solvent at a concentration of 0.5 M relative to 1a (entry 2).
Maumy had also chosen DBU as base, which is more effective than
triethylamine, DBED or cesium carbonate (entries 5e7), but had
employed a full equivalent and used a 3:1 mixture of acetonitrile
and propionitrile as solvent.
The transformation of 4-aryloxy-ortho-quinones into para-
alkoxyquinones is not known, so we began by investigating the
substitution with MeOH under acidic conditions (Table 1). In the
presence of 10 mol % para-toluene sulfonic acid (TsOH, pKa ꢀ2.8),
t
hedral intermediate adjacent to the Bu-group of the quinone fol-
lowing 1,4 addition under basic conditions. Under acidic conditions,
1,2-addition to the quinone carbonyl is less sterically demanding,
but is sensitive to the nucleophilicity of the alcohol (see Scheme 4
for details).
Substituted quinones lacking enolizable protons are tolerated
under our standard reaction conditions (Table 3, 2kem, 3kem),
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
3
Scheme 1. Previous syntheses of ortho- and para-alkoxyquinones and para-hydroxyquinones.
whereas those bearing enolizable protons require modified con-
ditions (1eeg). iso-Propyl or cyclcohexyl substituents are in-
compatible with the TfOH catalyst, but with catalytic amounts of
TsOH, para-quinones (2n, 2o) are obtained in good yields. These
quinones, which possess 3ꢁ CeH bonds, are compatible with the
DBU catalyzed conditions, but this is not the case for ortho-quinone
1g. When the enolizable protons are 2ꢁ and constrained within
a ring, basic conditions are no longer tolerated (2p), but sub-
stitution catalyzed by TsOH is (3p). As Maumy had previously
demonstrated, selective substitution of an aryloxy group when
there is an additional oxygen substituent is possible (2q, 2r),20 but
this class of substrate is incompatible with substitution under
acidic conditions (3q, 3r).
For reasons that remain unclear, the copper catalyst used to
synthesize the coupled ortho-quinones 1aei negatively impacts the
substitution chemistry, which requires that we purify the coupled
ortho-quinone prior to substitution. So far, this has prevented
a high-yielding, one-pot process to the alkoxyquinones from the
phenols. In contrast, hydrolysis of the coupled ortho-quinone is not
sensitive to the copper catalyst, and a one-pot process affording
para-hydroxyquinones is possible, following an appropriate aque-
ous acidic work-up. Under optimized conditions, phenol 4a is
Scheme 2. A two-step strategy for the synthesis of isomeric quinones from phenols.
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
Table 1
observed trends in reactivity and selectivity under our reaction
conditions.
Optimization of the substitutiona
3. Conclusion
In summary, we have developed an operationally simple, two-
step synthesis of ortho- and para-alkoxyquinones, as well as a one-
pot synthesis of para-hydroxyquinones beginning from a single
phenol starting material. In their development of quinone catalysts
for the oxidation of amines, Stahl and Luo were limited by the
availability of quinones for the purposes of screening and reaction
optimization. We hope that our strategy can alleviate this con-
straint, and afford a practical means of fine tuning catalyst perfor-
mance. In the context of a late stage-functionalization, we hope
that our methodology can provide a mild and efficient means of
diversifying the phenol pharmacophore.
Entry Catalyst
Solvent Conversionb (%) Yield of 2ab (%) Yield of 3aa (%)
ortho-Quinone
1
2
3
4
5
6
7
DBU
DBU
DBU
DBU
NEt3
DBED
Cs2CO3
CH2Cl2
THF
73
100
88
64
94
80
66
17
45
63
0
0
0
0
0
0
0
MeCN
EtOAc
THF
100
29
THF
47
THF
100
4. Experimental section
para-Quinone
8
9
TsOH$H2O CH2Cl2 100
0
0
11
4
5
0
19
<1
20
<1
0
83
4
25
4
4.1. General experimental procedures
TsOH$H2O THF
15
46
15
28
10
11
12
13
14
15
16
17
18
TsOH$H2O MeCN
TsOH$H2O Me2CO
TsOH$H2O EtOAc
Chemicals and solvents were purchased from Sigma Aldrich,
Alfa Aesar, Strem Chemicals or TCI. Solvents were dried and puri-
fied using a PureSolv MD 7 (from Innovative Technology) or MB SPS
800 (from MBraun). We have not observed differences in the re-
action outcome using either of these solvent purifiers. Unless
otherwise noted, reactions were performed in flame-dried glass-
ware under a positive pressure of nitrogen using standard syn-
thetic organic, inert atmosphere techniques. Proton nuclear
magnetic resonance (1H NMR) spectra were acquired using Varian
500 MHz, Bruker Ascend 500 MHz, Bruker Ascend 400 MHz, Varian
Inova 400 MHz and Varian Mercury 300 MHz spectrometers.
9
TfOH
CH2Cl2 100
94
58
<1
20
<1
63
CSA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90
1
48
4
AgOTf
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
CH2Cl2 100
a
Reactions were carried out using 0.5 mmol of 1a.
NMR yield was detected using hexamethylbenzene as internal standards.
b
oxidized to 1a under standard conditions in CH2Cl2. The reaction
mixture is then diluted with THF, and a 2:1 by volume mixture of
concentrated H2SO4 and H2O is added. After 1 h at room temper-
ature, 5a is obtained in high purity by acidebase extraction, and
phenol 4a is recovered quantitatively (Table 4, entry 8). We note
that the efficiency of this process is not affected by running the
hydrolysis under O2 (entry 7), reflecting the stability of quinone 5a
to Cu and O2 under acidic conditions. This is noteworthy, given the
observations of Sayre and co-workers that related compounds af-
ford complex mixtures when exposed to Cu and O2 under basic
conditions.18g
The scope of this one-pot procedure is good for a range of
phenols, including those bearing 3ꢁ benzylic hydrogen atoms
(Table 5, 4be4d). Likewise, aryl-, naphthyl-, and quaternary sub-
stituents are all tolerated (4ee4g), and 3-tert-butyl phenol (4j)
performs as well as its para-isomer 4a. Nevertheless, cyclic 2ꢁ
benzylic hydrogen atoms remain problematic and quinone 4k is
only isolated in low yield.
In the context of a late-stage functionalization, our methodology
offers a practical strategy for the selective diversification of the
phenol functional group (Scheme 3). For example, estrone is con-
verted into ortho- or para-alkoxyquinones 2s and 3s, or into para-
hydroxyquinone 5k in an operationally simple, two-step pro-
cedure. Metabolites of estrone related to 2s have been implicated in
the on-set of breast cancer, which has stimulated interest into ox-
idized forms of the hormone.22
Chemical shifts (d) are reported in parts per million (ppm) and are
calibrated to the residual solvent peak. Coupling constants (J) are
reported in hertz (Hz). Multiplicities are reported using the fol-
lowing abbreviations: s¼singlet; d¼doublet; t¼triplet; q¼quartet;
m¼multiplet (range of multiplet is given). Carbon nuclear mag-
netic resonance (13C NMR) spectra were acquired using Varian
125 MHz, Bruker Ascend 125 MHz, Bruker Ascend 100 MHz, Varian
Inova 100 MHz and Varian Mercury 75 MHz spectrometers.
Chemical shifts (
calibrated to the residual solvent peak. Chemical shifts (
d
) are reported in parts per million (ppm) and are
) are re-
d
ported in parts per million (ppm). Coupling constants (J) are re-
ported in hertz (Hz). Multiplicities are reported using the following
abbreviations: s¼singlet; d¼doublet; t¼triplet; q¼quartet;
m¼multiplet (range of multiplet is given). High-resolution mass
spectra (HRMS) were recorded using a Bruker maXis Impact TOF
mass spectrometer by electrospray ionization time of flight
reflectron experiments. Fourier-transform infrared (FTIR) spectra
were recorded on a Thermo Scientific Nicolet 6700 FT-IR spec-
trometer. Analytical thin-layer chromatography was performed on
pre-coated 250 mm layer thickness silica gel 60 F254 plates (EMD
Chemicals Inc.). Visualization was performed by ultraviolet light
and/or by staining with potassium permanganate or cerium mo-
lybdate. Purifications by column chromatography were performed
using standard column chromatography using silica gel
(40e63 mm, 230e400 mesh).
The isomerization of ortho-quinone 2a into para-quinone 3a in
the presence of catalytic amounts of TfOH and MeOH demonstrates
that the para-quinone isomer is thermodynamically favored
(Scheme 4). Whether ortho-quinone 2a is the kinetic product of
substitution under acidic conditions is unclear, but results with CSA
(Table 1, entry 14) suggest that its formation is competitive with
formation of the para-isomer. Based on these observations, we
propose the mechanism outlined in Scheme 4 to account for the
4.2. Synthetic procedures and characterization data
General procedure A: alcohol substitution under basic conditions
(2aet): A flame-dried, 5 mL microwave vial equipped with a Tef-
lon-coated stir bar and a rubber septum was charged with the
quinone 1 (1.0 mmol, 1.0 equiv) and the alcohol (1.2 mmol,
1.2 equiv) and then purged with a steady stream of N2 for 5 min,
prior to the addition of dry and degassed THF (2 mL). DBU
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
5
Table 2
Scope of the alcohola
[a] Condition A: 1a (1 mmol), DBU (0.1 mmol, 10 mol%) and the alcohol (1.2 mmol) was
reacted in THF (2 mL, 0.5 M) for the indicated amount of time at room temperature. Condition
B: 1a (1 mmol), TfOH (0.1 mmol, 10 mol%) and the alcohol (1.2 mmol) was reacted in CH2Cl2
(2 mL, 0.5 M) for the indicated amount of time at room temperature. [b] DBU (0.2 mmol, 20
mol%) was used.
(0.1 mmol, 15.0
m
L, 10 mol %) was then added dropwise to the re-
a Teflon-coated stir bar and a rubber septum was charged with the
quinone 1 (1.0 mmol, 1.0 equiv) and the alcohol (1.2 mmol,
1.2 equiv) and then purged with a steady stream of N2 for 5 min,
prior to the addition of dry and degassed CH2Cl2 (2 mL). TfOH
action mixture with a micro-syringe. The reaction mixture was
then stirred at room temperature (20e23 ꢁC) for 4 h. It was then
poured on NaHSO4 (10% by weight, 20 mL) and extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic fractions were dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by silica gel column chromatography using a mixture of
hexanes/ethyl acetate as eluant to afford the desired ortho-alkox-
yquinone product.
(0.1 mmol, 8.8 mL, 10 mol %) was then added dropwise to the re-
action mixture with a micro-syringe. The reaction mixture was
then stirred at room temperature (20e23 ꢁC) for 4 h. It was then
poured on NaHSO4 (10% by weight, 20 mL) and extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic fractions were dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by silica gel column chromatography using a mixture of
General procedure B: alcohol substitution under acidic conditions
(2aet): A flame-dried, 5 mL microwave vial equipped with
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6
Z. Huang et al. / Tetrahedron xxx (2015) 1e15
Table 3
Substrate scope for the quinonea
[a] Condition A: quinone 1 (1 mmol), DBU (0.1 mmol, 10 mol%) and methanol (1.2 mmol) was
reacted in THF (2 mL, 0.5 M) for 4h at room temperature. Condition B: quinone 1 (1 mmol),
TfOH (0.1 mmol, 10 mol%) and the alcohol (1.2 mmol) was reacted in CH2Cl2(2 mL, 0.5 M) for
4h at room temperature. [b] TsOH monohydrate (0.1 mmol, 10 mol%) was used instead of TfOH.
[c] MeOH (1 mmol) was used.
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
7
Table 4
Optimization of a 1-pot synthesis of para-hydroxyquinones
Entrya
Solvent
Hþ/H2O
Yield of 1ab (%)
Yield of 5ab (%)
Yield of 5a brsmb (%)
1
2
3
4
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
HCl (concd, 1.25 mL)
HCl (1:1 aq, 1.25 mL)
HCl (concd, 0.5 mL)
H2SO4 (2:1 aq, 1.25 mL)
HOAc (2:1 aq, 1.25 mL)
H2S04 (2:1 aq, 1.25 mL)
H2SO4 (2:1 aq, 1.25 mL)
H2SO4 (2:1 aq, 1.25 mL)
0
44
0
0
93
0
42
19
34
46
0
40
45
50
84
25
62
99
0
74
99
>99
5
6C
7d
8
0
0
a
Reactions were carried out using 0.5 mmol of 4a.
NMR yield was detected using hexamethylbenzene as internal standards.
The hydrolysis step was performed in THF (1 mL).
b
c
d
The hydrolysis step was performed under O2 (1 atm).
hexanes/ethyl acetate as eluant to generate the desired para-
alkoxyquinone product.
a Teflon-coated stir bar and a rubber septum was charged with the
phenol (1.0 equiv) and then purged with a steady stream of N2 for
5 min, prior to the addition of dry and degassed CH2Cl2 (1 M). In
General procedure C: synthesis of para-hydroxyquinones (5aek):
A flame-dried, 25 mL Radley tube equipped with a Teflon-coated
stir bar and a rubber septum was charged with the phenol
(1.0 mmol, 1.0 equiv) and then purged with a steady stream of N2
for 5 min, prior to the addition of dry and degassed CH2Cl2 (1 mL).
In a separate, flame-dried 5 mL microwave vial [Cu(CH3CN)4](PF6)
(0.04 mmol, 14.9 mg, 4 mol %) and N,N0-di-tert-butylethylenedi-
a
separate,
flame-dried
50
mL
round-bottom
flask
[Cu(CH3CN)4](PF6) (4e10 mol %) and DBED (N,N0-di-tert-butyle-
thylenediamine) (5e20 mol %) were dissolved in CH2Cl2 (0.04 M) to
afford a homogeneous pink solution. This solution was then added
to the Radley tube via syringe to afford a final concentration
0.1e0.5 M with respect to phenol. The flask was then connected to
a tank of O2 and pressurized to 1 atm. Under a constant pressure of
O2 (1 atm), the reaction was vented three times for 10 s to remove
N2. A dramatic color change was observed within 2 min, resulting in
a blackish/brown reaction mixture. The reaction mixture was then
stirred at room temperature (20e23 ꢁC) for 4 h, depressurized by
opening to the atmosphere and quenched by the addition of a 10%
aqueous solution of NaHSO4 (10 mL for 1 mmol reaction). The
mixture was extracted with CH2Cl2 (3ꢂ10 mL for 1 mmol reaction).
The combined organic layers were dried with MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by silica gel
column chromatography using hexanes/EtOAc as eluant to afford
the corresponding ortho-quinones.
amine (0.05 mmol, 10.8
mL, 5 mol %) were dissolved in CH2Cl2
(1.0 mL, 0.04 M) to afford a homogeneous pink solution. This
solution was then added to the Radley tube via syringe to afford
a final volume of 2.0 mL and a concentration 0.5 M with respect to
phenol. The rubber septum was then rapidly removed and
replaced with a Radley cap, which was connected to a tank of O2
and pressurized to 1 atm. Under a constant pressure of O2 (1 atm),
the reaction was vented three times for 10 s to remove N2. A
dramatic color change was observed within 2 min, resulting in
a blackish/brown reaction mixture. The reaction mixture was then
stirred at room temperature (20e23 ꢁC) for 4 h, depressurized by
opening to the atmosphere and the Radley cap was replaced by
a rubber septum. The Radley tube was purged with N2 for 5 min,
before the addition of THF (5 mL). The mixture was then cooled to
4.2.1. Compound 2a. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 159.2 mg,
0
ꢁC in an ice/water bath, at which temperature H2SO4 (2:1
mixture by volume of concentrated H2SO4 with water, 2.5 mL)
was added dropwise over a period of 5 min. The reaction mixture
was then warmed to room temperature and stirred for 1 h, before
quenching by the addition of water (20 mL). The mixture was
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic layer
was then extracted with a saturated aqueous solution of NaHCO3
(3ꢂ20 mL), and the combined NaHCO3 layers were washed with
CH2Cl2 (20 mL). The combined CH2Cl2 layers were dried over
MgSO4, filtered, and concentrated in vacuo to recover the starting
material phenol. The combined NaHCO3 layer was then acidified
with concentrated HCl dropwise until the color changed from red
to yellow (pH<2). The acidified aqueous layer was then extracted
with CH2Cl2 (3ꢂ50 mL), dried over MgSO4, filtered, and concen-
trated in vacuo to generate the desired para-hydroxyquinone
product.
82% yield, red solid. 1H NMR (500 MHz, CDCl3)
d
6.31 (s, 1H), 5.79 (s,
1H), 3.91 (s, 3H), 1.33 (s, 9H); 13C NMR (126 MHz, CDCl3)
d
181.6,
178.8,170.7,158.9,125.9,103.4, 56.4, 36.4, 29.7. The characterization
data match the previous report.23
4.2.2. Compound 3a. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
160.8 mg, 83% yield, orange solid. 1H NMR (500 MHz, CDCl3)
d
6.54
(s, 1H), 5.86 (s, 1H), 3.80 (s, 3H), 1.29 (s, 9H); 13C NMR (126 MHz,
CDCl3)
d 187.5, 183.1, 157.5, 156.9, 129.6, 109.6, 56.1, 35.4, 29.4. The
characterization data match the previous report.13b
4.2.3. Compound 2b. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 145.8 mg,
70% yield, red solid. 1H NMR (500 MHz, CDCl3)
d 6.30 (s, 1H), 5.76 (s,
General procedure D: synthesis of homo-coupled quinones (1aej):
A flame-dried, 250 mL round-bottom flask equipped with
1H), 4.10 (q, J¼7.0 Hz, 2H), 1.53 (t, J¼7.0 Hz, 3H), 1.34 (s, 9H); 13C
21
NMR (126 MHz, CDCl3) d 181.6, 178.8, 169.7, 159.1, 125.9, 103.6, 65.8,
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
Table 5
Scope of phenols for the synthesis of para-hydroxyquinonesa
[a] Condition: 4 (1 mmol), [Cu(MeCN)4](PF6) (0.04 mmol), DBED (0.05 mmol) was reacted in
CH2Cl2 (2 mL, 0.5 M) under O2 (1 atm) at rt for 4h. Then THF (5 mL) and H2SO4 (2:1 volume
mixture with water, 2.5 mL) was added at 0 oC, and stirred at rt for another 1h. Isolated yields are
reported first, followed by yields based on the recovery of starting phenol reported in
parenthesis. [b] DBED (20 mol%) was used. [c] The oxidation was run in CH2Cl2 (5 mL, 0.2 M).
And solvent was removed before adding THF (5 mL).
36.4, 29.8, 14.0. The characterization data match the previous
report.24
166.3 mg, 80% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5):
0.44; IR (neat)
¼2959, 2924, 1666, 1642, 1622, 1588, 1487, 1411,
1360, 1229, 1215, 1179, 1154, 1108 cmꢀ1; 1H NMR (500 MHz, CDCl3)
6.54 (s, 1H), 5.83 (s, 1H), 3.99 (q, J¼7.0 Hz, 2H), 1.47 (t, J¼7.0 Hz,
3H), 1.29 (s, 9H); 13C NMR (126 MHz, CDCl3)
187.7, 183.2, 156.8,
n
4.2.4. Compound 3b. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
d
d
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
9
Scheme 3. Selective oxygenation of estrone. [a] Conditions for the oxidation of estrone: estrone (1 mmol), [Cu(MeCN)4](PF6) (0.1 mmol, 10 mol %) and DBED (0.125 mmol,
12.5 mol %) was reacted under O2 (1 atm) in CH2Cl2 (10 mL, 0.1 M) at room temperature for 4 h. Condition for basic substitution: 1j (0.2 mmol), DBU (0.02 mmol, 10 mol %), and
MeOH (0.24 mmol) were reacted in THF (0.4 mL, 0.5 M) at room temperature for 4 h. Condition for acidic substitution: 1j (0.2 mmol), TsOH monohydrate (0.02 mmol, 10 mol %), and
MeOH (0.24 mmol) were reacted in CH2Cl2 (0.4 mL, 0.5 M) at room temperature for 4 h. Condition for hydrolysis: 1j (0.2 mmol) and H2SO4 (2:1 volume mixture with water, 0.5 mL)
were reacted in THF (1 mL, 0.2 M) at room temperature for 1 h.
Scheme 4. Proposed mechanism for the substitution of aryloxy-quinones with alcohols. [a] Conditions for the rearrangement of 2a to 3a: 2a (0.2 mmol), TfOH (0.02 mmol,
10 mol %), and MeOH (0.24 mmol) were reacted in CH2Cl2 (0.4 mL, 0.5 M) at room temperature for 4 h.
156.7, 129.7, 109.9, 65.0, 35.3, 29.4, 13.9; HRMS: calcd for C12H16O3
184.0 mg, 84% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5):
0.54; IR (neat)
¼2926, 2870, 1666, 1640, 1622, 1588, 1485, 1367,
1349, 1213, 1177, 1125 cmꢀ1 1H NMR (500 MHz, CDCl3)
6.56 (s,
[M]-¼208.1105 m/z, found¼208.1098 m/z.
n
;
d
4.2.5. Compound 2c. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 195.6 mg,
89% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.50; IR (neat)
1H), 6.02 (ddt, J¼17.2, 10.6, 5.6 Hz, 1H), 5.86 (s, 1H), 5.44 (ddd,
J¼17.2, 2.6, 1.4 Hz, 1H), 5.38 (dd, J¼10.5, 1.1 Hz, 1H), 4.51 (dt, J¼5.6,
1.1 Hz, 2H), 1.30 (s, 9H); 13C NMR (126 MHz, CDCl3)
d 187.6, 183.1,
n
¼3018, 2964, 2920, 2872, 1673, 1646, 1603, 1549, 1353, 1237, 1198,
156.7, 156.3, 130.6, 129.7, 119.9, 110.5, 69.8, 35.3, 29.4; HRMS: calcd
1172 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
6.26 (s, 1H), 6.02 (ddd,
for C13H16O3 [MþNa]þ¼243.0992 m/z, found¼243.1000 m/z.
J¼17.2, 10.5, 5.7 Hz, 1H), 5.74 (s, 1H), 5.45 (dd, J¼17.2, 1.0 Hz, 1H),
5.39 (dd, J¼10.5, 0.9 Hz, 1H), 4.56 (d, J¼5.7 Hz, 2H), 1.31 (s, 9H); 13
C
4.2.7. Compound 2d. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 158.1 mg,
72% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.44; IR (neat)
NMR (126 MHz, CDCl3) d 181.5,178.7,169.3,159.1, 130.1,125.9,120.4,
104.1, 70.6, 36.4, 29.7; HRMS: calcd for
C13H16O3
[MþNa]þ¼243.0992 m/z, found¼243.0997 m/z.
n
¼3271, 2971, 2873, 2134, 1681, 1650, 1604, 1550, 1390, 1349, 1315,
1281, 1234, 1202, 1176 cmꢀ1
1H), 5.85 (s, 1H), 4.75 (d, J¼2.4 Hz, 2H), 2.68 (t, J¼2.4 Hz, 1H), 1.33 (s,
9H); 13C NMR (126 MHz, CDCl3)
181.1, 178.6, 168.2, 158.9, 125.9,
; d 6.30 (s,
1H NMR (500 MHz, CDCl3)
4.2.6. Compound 3c. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
d
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10
Z. Huang et al. / Tetrahedron xxx (2015) 1e15
104.6, 78.0, 75.2, 56.9, 36.4, 29.7; HRMS: calcd for C13H14O3
n
¼2959, 2876, 1739, 1681, 1640, 1606, 1548, 1377, 1348, 1278, 1240,
[MþNa]þ¼241.0835 m/z, found¼241.0846 m/z.
1198, 1163 cmꢀ1; 1H NMR (500 MHz, acetone-d6)
d
6.22 (s, 1H), 5.77
(s, 1H), 5.01 (tt, J¼5.8, 2.8 Hz, 1H), 2.12e2.04 (m, 2H), 2.00e1.94 (m,
4.2.8. Compound 3d. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
117.5 mg, 54% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5):
2H), 1.88e1.80 (m, 2H), 1.79e1.73 (m, 2H), 1.36 (s, 9H); 13C NMR
(126 MHz, acetone-d6) d 181.5, 178.3, 167.9, 158.5, 125.8, 104.4, 82.4,
35.8, 32.2, 29.1, 23.8; HRMS: calcd for C15H20O3 [MþNa]þ¼271.1305
m/z, found¼271.1310 m/z.
0.42; IR (neat)
n
¼3309, 3062, 2960, 2139, 1663, 1642, 1624, 1588,
1485, 1357, 1344, 1270, 1230, 1210, 1175 cmꢀ1 1H NMR (500 MHz,
;
CDCl3)
d
6.57 (s, 1H), 6.04 (s, 1H), 4.70 (d, J¼2.4 Hz, 2H), 2.64 (t,
4.2.15. Compound 3h. Synthesized according to the general pro-
cedure B. Purified with 10% EtOAc/hexanes on silica gel. 215.4 mg,
87% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:10): 0.33; IR
J¼2.4 Hz, 1H), 1.30 (s, 9H); 13C NMR (126 MHz, CDCl3)
d 187.3, 182.7,
156.7,155.2,129.8,111.3, 78.0, 75.5, 56.5, 35.4, 29.4; HRMS: calcd for
C
13H14O3 [MþNa]þ¼241.0835 m/z, found¼241.0841 m/z.
(neat)
n
¼2960, 2869, 1668, 1637, 1622, 1590, 1483, 1453, 1356, 1340,
1213, 1175 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d 6.50 (s, 1H), 5.80 (s,
4.2.9. Compound 2e. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 186.3 mg,
69% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.54; IR (neat)
1H), 4.61 (tt, J¼5.6, 2.9 Hz, 1H), 1.98e1.85 (m, 4H), 1.83e1.75 (m,
2H), 1.67e1.55 (m, 2H), 1.27 (s, 9H); 13C NMR (126 MHz, CDCl3)
d
187.7, 183.5, 156.4, 156.1, 129.8, 110.8, 81.4, 35.3, 32.3, 29.4, 24.1;
n
¼2961, 1674, 1649, 1609, 1554, 1484, 1456, 1396, 1369, 1349, 1278,
HRMS: calcd for C15H20O3 [MþNa]þ¼271.1305 m/z, found¼271.1311
m/z.
1240, 1199, 1173 cmꢀ1
5H), 6.33 (s, 1H), 5.90 (s, 1H), 5.09 (s, 2H), 1.31 (s, 9H); 13C NMR
(126 MHz, CDCl3) 181.5, 178.8, 169.4, 159.1, 133.6, 129.1, 129.0,
; d 7.49e7.38 (m,
1H NMR (500 MHz, CDCl3)
d
4.2.16. Compound 2i. Synthesized according to the general pro-
cedure A. Purified with 25% EtOAc/hexanes on silica gel. 94.2 mg,
36% yield, red solid. Rf¼(ethyl acetate/hexane 1:3): 0.36; IR (neat)
128.3, 126.0, 104.4, 72.2, 36.4, 29.7; HRMS: calcd for C17H18O3
[MþNa]þ¼293.1148 m/z, found¼293.1159 m/z.
n
¼2934, 2856, 1737, 1687, 1646, 1608, 1552, 1491, 1449, 1357, 1235,
4.2.10. Compound 3e. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
204.8 mg, 76% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:10):
1196 cmꢀ1 1H NMR (500 MHz, acetone-d6)
; d 6.22 (s, 1H), 5.83 (s,
1H), 4.62 (tt, J¼8.7, 4.0 Hz, 1H), 2.15e2.08 (m, 2H), 1.85e1.79 (m,
2H), 1.74e1.66 (m, 2H), 1.65e1.60 (m, 1H), 1.58e1.51 (m, 2H),
1.47e1.41 (m, 1H), 1.39 (s, 9H); 13C NMR (126 MHz, acetone-d6)
0.33; IR (neat)
1216, 1171 cmꢀ1
6.56 (s, 1H), 5.92 (s, 1H), 5.02 (s, 2H), 1.29 (s, 9H); 13C NMR
(126 MHz, CDCl3) 187.6, 183.0, 156.6, 156.4, 134.2, 129.8, 128.8,
n
¼2959, 1664, 1641, 1627, 1593, 1498, 1455, 1357,
;
1H NMR (500 MHz, CDCl3)
d
7.45e7.32 (m, 5H),
d 181.5, 178.5, 167.6, 158.6, 125.8, 103.8, 77.8, 35.9, 30.7, 29.2, 25.0,
23.2; HRMS: calcd for
found¼285.1468 m/z.
C
16H22O3 [MþNa]þ¼285.1461 m/z,
d
128.7, 127.7, 110.8, 70.8, 35.3, 29.4; HRMS: calcd for C17H18O3
[MþNa]þ¼293.1148 m/z, found¼293.1155 m/z.
4.2.17. Compound 3i. Synthesized according to the general pro-
cedure B. Purified with 10% EtOAc/hexanes on silica gel. 117.8 mg,
45% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:10): 0.36; IR
4.2.11. Compound 2f. Synthesized according to the general pro-
cedure A. Purified with 25% EtOAc/hexanes on silica gel. 176.2 mg,
67% yield, red solid. Rf¼(ethyl acetate/hexane 1:3): 0.40; IR (neat)
(neat)
n
¼2951, 2857, 1668, 1640, 1623, 1591, 1482, 1452, 1365, 1344,
1228,1212,1176 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 6.53 (s,1H), 5.83
n
¼2966, 1675, 1656, 1609, 1556, 1484, 1431, 1367, 1288, 1276, 1236,
(s, 1H), 4.15 (tt, J¼9.4, 3.9 Hz, 1H), 2.03e1.96 (m, 2H), 1.87e1.79 (m,
1155 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 6.35 (s, 1H), 5.73 (s, 1H),
2H), 1.64e1.55 (m, 3H), 1.39e1.27 (m, 12H); 13C NMR (126 MHz,
4.39 (q, J¼7.7 Hz, 2H), 1.35 (s, 9H); 13C NMR (126 MHz, CDCl3)
CDCl3) d 187.9, 183.6, 156.4, 155.6, 129.8, 110.2, 77.4, 35.3, 30.8, 29.4,
d
180.6, 178.4, 167.6, 158.1, 126.3, 122.3 (q, JF¼277.4 Hz), 104.4, 65.7
25.2, 23.7; HRMS: calcd for C16H22O3 [MþNa]þ¼285.1461 m/z,
found¼285.1464 m/z.
(q, JF¼37.1 Hz), 36.4, 29.4; HRMS: calcd for C12H13F3O3
[MþNa]þ¼285.0709 m/z, found¼285.0718 m/z.
4.2.18. Compound 3j. Synthesized according to the general pro-
cedure B. Purified with 5% EtOAc/hexanes on silica gel. 318.0 mg,
99% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:20): 0.33; IR
4.2.12. Compound 2g. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 99.5 mg,
45% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.48; IR (neat)
(neat)
n
¼2950, 2923, 2867, 1670, 1638, 1624, 1591, 1457, 1367, 1334,
n
¼2874, 1684, 1647, 1607, 1550, 1451, 1368, 1325, 1278, 1246, 1200,
1214, 1174 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 6.53 (s, 1H), 5.86 (s,
1174, 1100 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
6.28 (s, 1H), 5.74 (s,
1H), 3.97 (td, J¼10.6, 4.1 Hz, 1H), 2.12e2.00 (m, 2H), 1.76e1.66 (m,
3H),1.49e1.41 (m,1H),1.29 (s, 9H),1.12e1.04 (m, 2H), 0.97e0.89 (m,
1H), 4.62 (hept, J¼6.1 Hz, 1H), 1.44 (d, J¼6.1 Hz, 6H), 1.32 (s, 9H); 13
C
NMR (126 MHz, CDCl3)
d
181.7, 178.8, 168.5, 159.4, 126.0, 103.9, 73.2,
7H), 0.74 (d, J¼7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3)
d 188.0,183.5,
36.3, 29.8, 21.3; HRMS: calcd for C13H18O3 [MþNa]þ¼245.1148 m/z,
found¼245.1156 m/z.
156.4, 156.0, 129.9, 109.6, 79.1, 47.0, 38.5, 35.3, 34.1, 31.4, 29.4, 26.1,
23.6, 21.9, 20.5,16.5; HRMS: calcd for C20H30O3 [MþNa]þ¼341.2087
m/z, found¼341.2086 m/z.
4.2.13. Compound 3g. Synthesized according to the general pro-
cedure B. Purified with 10% EtOAc/hexanes on silica gel. 192.4 mg,
87% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:10): 0.39; IR
4.2.19. Compound 2k. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 243.0 mg,
95% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.43; IR (neat)
(neat)
n
¼1289, 1668, 1638, 1621, 1589, 1454, 1367, 1226, 1212, 1173,
1105 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
6.53 (s, 1H), 5.81 (s, 1H),
n
¼3066, 2971, 1676, 1651, 1560, 1494, 1441, 1368, 1250, 1179,
4.44 (hept, J¼6.1 Hz,1H),1.39 (d, J¼6.1 Hz, 6H),1.28 (s, 9H); 13C NMR
1137 cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.21e7.16 (m, 3H), 6.54 (s, 1H), 5.66 (s, 1H), 3.42 (s, 3H), 1.60 (s, 6H);
13C NMR (126 MHz, CDCl3)
181.5, 178.6, 169.8, 158.2, 147.3, 128.5,
d
7.29 (dd, J¼8.2, 7.2 Hz, 2H),
(126 MHz, CDCl3) d 187.8, 183.6, 156.5, 155.7, 129.8, 110.2, 72.0, 35.3,
29.4, 21.1; HRMS: calcd for C13H18O3 [MþNa]þ¼245.1148 m/z,
found¼245.1158 m/z.
d
126.2, 126.0, 124.6, 103.7, 56.0, 43.2, 29.4; HRMS: calcd for C16H16O3
[MþNa]þ¼279.0992 m/z, found¼279.1000 m/z.
4.2.14. Compound 2h. Synthesized according to the general pro-
cedure A. Purified with 25% EtOAc/hexanes on silica gel. 147.0 mg,
59% yield, red solid. Rf¼(ethyl acetate/hexane 1:3): 0.36; IR (neat)
4.2.20. Compound 3k. Synthesized according to the general pro-
cedure B. Purified with 10e20% EtOAc/hexanes on silica gel.
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Z. Huang et al. / Tetrahedron xxx (2015) 1e15
11
206.3 mg, 80% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5):
0.23; IR (neat)
¼2974, 1665, 1644, 1630, 1599, 1495, 1361, 1240,
1205, 1174, 1133 cmꢀ1; 1H NMR (500 MHz, CDCl3)
7.30 (t, J¼7.6 Hz,
2H), 7.23 (d, J¼7.4 Hz, 2H), 7.19 (t, J¼7.2 Hz, 1H), 6.78 (s, 1H), 5.77 (s,
1H), 3.78 (s, 3H), 1.62 (s, 6H); 13C NMR (126 MHz, CDCl3)
186.4,
81% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.34; IR (neat)
¼2923, 2852, 1662, 1645, 1564, 1443, 1391, 1358, 1326, 1244,
1163 cmꢀ1; 1H NMR (500 MHz, CDCl3)
n
n
d
d
6.21 (d, J¼0.6 Hz, 1H), 5.76
(s, 1H), 3.89 (s, 3H), 2.65 (t, J¼11.7 Hz, 1H), 1.90e1.80 (m, 4H),
d
1.79e1.72 (m, 1H), 1.43e1.33 (m, 2H), 1.27e1.15 (m, 3H); 13C NMR
183.1, 157.7, 156.0, 147.3, 130.1, 128.4, 126.0, 125.3, 109.2, 56.2, 42.1,
(126 MHz, CDCl3) d 180.8, 178.8, 168.8, 157.8, 125.4, 102.7, 56.9, 37.8,
29.1; HRMS: calcd for
C
16H16O3 [MþNa]þ¼279.0992 m/z,
32.3, 26.4, 25.9; HRMS: calcd for C13H16O3 [MþNa]þ¼243.0992 m/z,
found¼243.0998 m/z.
found¼279.0999 m/z.
4.2.21. Compound 2l. Synthesized according to the general pro-
cedure A. Purified with 50% EtOAc/hexanes on silica gel. 190.1 mg,
80% yield, red solid. Rf¼(ethyl acetate/hexane 1:1): 0.29; IR (neat)
4.2.28. Compound 3o. Synthesized according to the general pro-
cedure B. Purified with 20% EtOAc/hexanes on silica gel. 182.1 mg,
83% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5): 0.30; IR
n
¼1731, 1681, 1648, 1573, 1371, 1278, 1248,1174,1150, 1136 cmꢀ1; 1H
(neat)
n
¼2919, 1666, 1640, 1599, 1442, 1373, 1230, 1208, 1174 cmꢀ1
;
NMR (500 MHz, CDCl3)
d
6.31 (s, 1H), 5.77 (s, 1H), 3.81 (s, 3H), 3.65
1H NMR (500 MHz, CDCl3)
d
6.44 (d, J¼1.0 Hz, 1H), 5.93 (s, 1H), 3.82
(s, 3H), 1.44 (s, 6H); 13C NMR (126 MHz, CDCl3)
d
180.7, 178.2, 175.0,
(s, 3H), 2.73 (tdd, J¼11.8, 2.8, 2.3 Hz, 1H), 1.85e1.72 (m, 5H),
168.3, 154.3, 125.6, 103.3, 56.8, 52.4, 45.2, 25.2; HRMS: calcd for
1.46e1.35 (m, 2H), 1.27e1.11 (m, 3H); 13C NMR (126 MHz, CDCl3)
C
12H14O5 [MþNa]þ¼261.0733 m/z, found¼261.0735 m/z.
d 187.1, 182.8, 158.3, 155.0, 128.8, 107.9, 56.2, 36.3, 32.2, 26.3, 26.0;
HRMS:
found¼243.1000 m/z.
calcd
for
C13H16O3
[MþNa]þ¼243.0992
m/z,
4.2.22. Compound 3l. Synthesized according to the general pro-
cedure B. Purified with 30% EtOAc/hexanes on silica gel. 205.3 mg,
86% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:2): 0.33; IR
4.2.29. Compound 3p. Synthesized according to the general pro-
cedure B. Purified with 20% EtOAc/hexanes on silica gel. 148.0 mg,
(neat)
1182, 1138 cmꢀ1
1H), 3.80 (s, 3H), 3.61 (s, 3H), 1.40 (s, 6H); 13C NMR (126 MHz,
n
¼2948, 1744, 1669, 1644, 1601, 1458, 1364, 1280, 1256, 1204,
;
1H NMR (500 MHz, CDCl3)
d
6.55 (s, 1H), 5.90 (s,
77% yield, yellow solid. 1H NMR (500 MHz, CDCl3)
d
5.81 (s, 1H),
3.77 (s, 3H), 2.45e2.31 (m, 4H), 1.72e1.58 (m, 4H); 13C NMR
(126 MHz, CDCl3) 187.4, 182.1, 158.4, 143.0, 140.3, 106.9, 56.1, 22.7,
CDCl3)
d
186.3,182.3,175.5,158.3,152.7,129.0,108.1, 56.3, 52.3, 44.0,
d
25.1; HRMS: calcd for
found¼261.0737 m/z.
C
12H14O5 [MþNa]þ¼261.0733 m/z,
22.3, 21.1, 21.0. The characterization data match the previous
report.26
4.2.23. Compound 2m. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 115.7 mg,
54% yield, red solid. Rf¼(ethyl acetate/hexane 1:1): 0.46; IR (neat)
4.2.30. Compound 2q. Synthesized according to the general pro-
cedure A. Purified with 70% EtOAc/hexanes on silica gel. 125.0 mg,
74% yield, orange solid. 1H NMR (500 MHz, CDCl3)
d
5.77 (s, 2H),
n
¼1643, 1560, 1373, 1243, 1163 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
3.91 (s, 6H); 13C NMR (126 MHz, CDCl3)
d 178.9, 163.7, 103.0, 57.1.
d
7.52e7.42 (m, 5H), 6.43 (s, 1H), 5.93 (s, 1H), 3.91 (s, 3H); 13C NMR
The characterization data match the previous report.27
(126 MHz, CDCl3)
d 180.2, 178.7, 168.1, 150.7, 133.7, 130.1, 128.99,
128.96, 128.4, 103.3, 57.1; HRMS: calcd for
C
13H10O3
4.2.31. Compound 2r. Synthesized according to the general pro-
cedure A. Purified with 50% EtOAc/hexanes on silica gel. 130.7 mg,
57% yield, orange solid. Rf¼(ethyl acetate/hexane 1:1): 0.32; IR
[MþNa]þ¼237.0522 m/z, found¼237.0519 m/z.
4.2.24. Compound 3m. Synthesized according to the general pro-
cedure B. Purified with 20% EtOAc/hexanes on silica gel. 203.8 mg,
(neat)
n
¼1663, 1646, 1579, 1486, 1459, 1388, 1274, 1223, 1154 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.47 (t, J¼8.0 Hz, 2H), 7.33 (t, J¼7.5 Hz,
95% yield, yellow solid. 1H NMR (500 MHz, CDCl3)
d
7.53e7.42 (m,
1H), 7.11 (d, J¼7.7 Hz, 2H), 5.85 (s, 1H), 5.47 (s, 1H), 3.99 (s, 3H); 13
C
5H), 6.83 (s, 1H), 6.07 (s, 1H), 3.89 (s, 3H); 13C NMR (126 MHz,
NMR (126 MHz, CDCl3) d 179.0, 178.7, 163.8, 163.6, 152.1, 130.5, 127.1,
CDCl3)
d
186.6, 182.2, 158.6, 146.5, 132.7, 130.9, 130.2, 129.5, 128.5,
120.9, 106.3, 103.2, 57.2; HRMS: calcd for
C13H10O4
108.0, 56.4. The characterization data match the previous report.25
[MþNa]þ¼253.0471 m/z, found¼253.0470 m/z.
4.2.25. Compound 2n. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 106.4 mg,
59% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.33; IR (neat)
4.2.32. Compound 5a. Synthesized according to the general pro-
cedure C: 84.7 mg, 47% yield, yellow solid; 72.1 mg recovery of 4a,
90% yield brsm. 1H NMR (500 MHz, CDCl3)
d
6.89 (br s, 1H), 6.61 (s,
n
¼1644, 1569, 1385, 1340, 1246, 1180, 1167 cmꢀ1
;
1H NMR
1H), 6.02 (s, 1H), 1.29 (s, 9H); 13C NMR (126 MHz, CDCl3)
d
187.8,
(500 MHz, CDCl3)
d
6.21 (d, J¼1.0 Hz, 1H), 5.75 (s, 1H), 3.88 (s, 3H),
184.3, 159.6, 153.3, 127.2, 110.0, 35.8, 29.5. The characterization data
match the previous report.14a
3.01 (heptd, J¼6.8, 1.1 Hz, 1H), 1.15 (d, J¼6.8 Hz, 6H); 13C NMR
(126 MHz, CDCl3) d 180.8, 178.8, 168.9, 158.9, 124.8, 102.7, 56.9, 27.9,
21.5; HRMS: calcd for
C
10H12O3 [MþNa]þ¼203.0679 m/z,
4.2.33. Compound 5b. Synthesized according to the general pro-
cedure C: 75.7 mg, 46% yield, yellow solid; 68.1 mg recovery of 4b,
found¼203.0681 m/z.
92% yield brsm. 1H NMR (300 MHz, CDCl3)
d
7.06 (br s, 1H), 6.54 (d,
4.2.26. Compound 3n. Synthesized according to the general pro-
cedure B. Purified with 20% EtOAc/hexanes on silica gel. 148.8 mg,
83% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:5): 0.33; IR
J¼1.1 Hz, 1H), 6.09 (s, 1H), 3.18e2.98 (m, 1H), 1.13 (d, J¼6.9 Hz, 6H);
13C NMR (75 MHz, CDCl3)
d 187.3, 184.0, 158.7, 154.1, 125.9, 108.5,
27.0, 21.6. The characterization data match the previous report.13b
(neat)
n
¼2964, 1663, 1640, 1600, 1469, 1457, 1446, 1367, 1312, 1232,
1208,1183,1171 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
6.47 (d, J¼1.1 Hz,
4.2.34. Compound 5c. Synthesized according to the general pro-
cedure C: 86.5 mg, 48% yield, yellow solid; 75.1 mg recovery of 4c,
96% yield brsm. Rf¼(ethyl acetate/hexane 1:1): 0.71; IR (neat)
1H), 5.93 (s, 1H), 3.82 (s, 3H), 3.07 (heptd, J¼6.9, 1.1 Hz, 1H), 1.13 (d,
J¼6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3)
d 187.1, 182.7, 158.3, 156.0,
128.4, 108.0, 56.2, 26.7, 21.5; HRMS: calcd for
C10H12O3
n
¼3256, 2965, 2933, 2876, 1652, 1634, 1606, 1463, 1383, 1334, 1317,
[MþNa]þ¼203.0679 m/z, found¼203.0674 m/z.
1297, 1205 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.14 (br s, 1H), 6.51 (s,
1H), 6.09 (s, 1H), 2.99e2.81 (m, 1H), 1.60e1.48 (m, 1H), 1.47e1.34
4.2.27. Compound 2o. Synthesized according to the general pro-
cedure A. Purified with 30% EtOAc/hexanes on silica gel. 177.6 mg,
(m, 1H), 1.09 (d, J¼6.9 Hz, 3H), 0.87 (t, J¼7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d 187.4, 183.9, 157.8, 154.1, 126.7, 108.4, 33.3, 28.8,
Please cite this article in press as: Huang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.095

12
Z. Huang et al. / Tetrahedron xxx (2015) 1e15
19.0, 11.6; HRMS: calcd for C10H12O3 [MꢀH]ꢀ¼179.0714 m/z,
found¼179.0705 m/z.
126.8, 108.8, 52.4, 44.4, 25.2; HRMS: calcd for C11H12O5
[MþNa]þ¼247.0577 m/z, found¼247.0579 m/z.
4.2.35. Compound 5d. Synthesized according to the general pro-
cedure C: 93.9 mg, 46% yield, yellow solid; 84.6 mg recovery of
4d, 88% yield brsm. Rf¼(ethyl acetate/hexane 1:2): 0.19; IR (neat)
4.2.41. Compound 5a prepared from 4j. Synthesized according to
the general procedure C: 86.7 mg, 48% yield, yellow solid; 72.1 mg
recovery of 4j, 92% yield brsm.
n
¼3086, 2924, 2850, 1675, 1651, 1604, 1446, 1391, 1376, 1309,
1236, 1213, 1178, 1141, 1103 cmꢀ1
7.00 (br s, 1H), 6.54 (d, J¼1.0 Hz, 1H), 6.11 (s, 1H), 2.78 (tt,
J¼12.0, 2.5 Hz, 1H), 1.88e1.75 (m, 5H), 1.49e1.36 (m, 2H),
1.26e1.11 (m, 3H); 13C NMR (75 MHz, CDCl3)
187.3, 184.0, 157.6,
;
1H NMR (400 MHz, CDCl3)
4.2.42. Compound 5j. Synthesized according to the general pro-
cedure C: 32.1 mg, 18% yield, yellow solid; 99.7 mg recovery of 4k,
d
55% yield brsm. 1H NMR (500 MHz, CDCl3)
d
7.13 (br s, 1H), 6.05 (s,
d
1H), 2.50e2.43 (m, 4H), 1.75e1.70 (m, 4H); 13C NMR (126 MHz,
154.1, 126.4, 108.4, 36.6, 32.3, 26.2, 25.9; HRMS: calcd for
CDCl3) d 187.8, 183.7, 154.2, 145.6, 138.4, 107.5, 23.0, 22.1, 21.0, 20.9.
C
12H14O3 [MþNa]þ¼229.0835 m/z, found¼229.0838 m/z. This
The characterization data match the previous report.28
compound was previous reported.19 However, we cannot find
characterization data.
4.2.43. Compound 1j. Synthesized according to the general pro-
cedure D. Purified with 40% EtOAc/hexanes on silica gel; 150.1 mg,
54% yield, red solid. Rf¼(ethyl acetate/hexane 1:1): 0.38; IR (neat)
4.2.36. Compound 5e. Synthesized according to the general pro-
cedure C: 63.2 mg, 32% yield, yellow solid; 98.0 mg recovery of 4e,
75% yield brsm. Rf¼(ethyl acetate/hexane 1:2): 0.13; IR (neat)
n
¼3456, 2970, 1564, 1439, 1380, 1353, 1213 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
7.36 (d, J¼8.3 Hz,1H), 6.84 (d, J¼7.9 Hz,1H), 6.80
n
¼3198, 1647, 1632, 1599, 1490, 1449, 1388, 1324, 1246, 1215,
(s, 1H), 5.42 (s, 1H), 2.93 (d, J¼4.2 Hz, 2H), 2.85e2.69 (m, 2H),
2.60e2.47 (m, 2H), 2.46e2.26 (m, 4H), 2.21e1.87 (m, 8H), 1.74e1.43
(m, 11H), 1.28e1.19 (m, 1H), 0.99 (s, 3H), 0.95 (s, 3H); 13C NMR
1180 cmꢀ1
; d 7.51e7.46 (m, 5H), 7.15
1H NMR (500 MHz, CDCl3)
(br s, 1H), 6.91 (s, 1H), 6.24 (s, 1H); 13C NMR (126 MHz, CDCl3)
d
187.0, 183.5, 154.5, 148.7, 132.8, 130.5, 129.7, 128.5, 128.4, 108.4;
(126 MHz, CDCl3) d 220.5, 219.6, 180.4, 179.2, 171.5, 149.8, 146.3,
139.3, 139.1, 138.8, 127.3, 121.0, 118.1, 104.3, 50.4, 49.8, 48.4, 47.9,
44.9, 44.1, 39.4, 38.0, 35.8, 35.6, 32.2, 31.5, 29.4, 26.8, 26.2, 25.8,
HRMS:
found¼223.0372 m/z.
calcd
for
C
12H8O3
[MþNa]þ¼223.0366
m/z,
24.5, 23.2, 21.6, 21.5, 14.4, 13.8; HRMS: calcd for
C36H40O5
4.2.37. Compound 5f. Synthesized according to the general pro-
cedure C: 106.9 mg, 46% yield, yellow solid; 96.8 mg recovery of
4f, 88% yield brsm. Rf¼(ethyl acetate/hexane 1:1): 0.26; IR (neat)
[MþH]þ¼553.2949 m/z, found¼553.2946 m/z.
4.2.44. Compound 2s. Synthesized according to the general pro-
cedure B. Purified with 30% EtOAc/hexanes on silica gel; 47.6 mg,
76% yield, red solid. Rf¼(ethyl acetate/hexane 2:1): 0.45; IR (neat)
n
¼3331, 1636, 1597, 1571, 1488, 1461, 1410, 1342, 1253, 1239, 1208,
1182, 1122 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.44 (td, J¼8.4,
1.7 Hz, 1H), 7.22 (br s, 1H), 7.18 (dd, J¼7.5, 1.7 Hz, 1H), 7.03 (td,
n
¼2926, 1734, 1646, 1566, 1454, 1374, 1341, 1229, 1209 cmꢀ1
;
1H
J¼7.5, 0.8 Hz, 1H), 6.99 (d, J¼8.3 Hz, 1H), 6.88 (s, 1H), 6.23 (s, 1H),
NMR (500 MHz, CDCl3)
d 5.71 (s, 1H), 3.87 (s, 3H), 2.79e2.66 (m,
3.81 (s, 3H); 13C NMR (126 MHz, CDCl3)
d
186.2, 183.7, 157.3,
1H), 2.58e2.46 (m, 2H), 2.33e2.11 (m, 3H), 2.06e1.99 (m, 1H), 1.89
(ddd, J¼13.1, 9.2, 4.3 Hz, 2H), 1.71e1.65 (m, 1H), 1.62e1.49 (m, 3H),
1.39 (ddd, J¼25.0, 13.2, 3.3 Hz, 1H), 1.14 (ddd, J¼24.4, 12.2, 4.6 Hz,
154.4, 148.5, 131.4, 130.8, 130.2, 122.6, 120.6, 111.4, 108.5, 55.8;
HRMS:
found¼253.0478 m/z.
calcd
for
C
13H10O4
[MþNa]þ¼253.0471
m/z,
1H), 0.96 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 219.7, 180.6, 179.1,
171.3, 146.9, 138.5, 100.8, 56.5, 49.9, 48.4, 44.9, 39.3, 35.6, 32.2, 26.9,
24.3, 23.2, 21.5, 14.4; HRMS: calcd for C19H22O4 [MþH]þ¼315.1591
m/z, found¼315.1584 m/z.
4.2.38. Compound 5g. Synthesized according to the general pro-
cedure C: 107.6 mg, 43% yield, yellow solid; 113.6 mg recovery of 4g,
90% yield brsm. Rf¼(ethyl acetate/hexane 1:1): 0.26; IR (neat)
n
¼3259, 3056, 1647, 1595, 1507, 1390, 1333, 1288, 1191 cmꢀ1
;
1H
4.2.45. Compound 3s. Synthesized according to the general pro-
cedure B. Purified with 30% EtOAc/hexanes on silica gel; 51.4 mg,
82% yield, yellow solid. Rf¼(ethyl acetate/hexane 1:2): 0.26; IR
NMR (500 MHz, CDCl3)
d
7.96 (d, J¼8.3 Hz, 1H), 7.92 (d, J¼7.5 Hz,
1H), 7.67 (d, J¼8.1 Hz, 1H), 7.58e7.47 (m, 3H), 7.36 (d, J¼7.0 Hz, 1H),
6.95 (s, 1H), 6.32 (s, 1H); 13C NMR (126 MHz, CDCl3)
187.0, 183.5,
154.8, 150.0, 133.5, 131.4, 131.4, 131.0, 130.3, 128.6, 127.7, 126.8,
d
(neat)
n
¼2961, 2923, 2852, 1735, 1671, 1642, 1597, 1457, 1230 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d 5.83 (s, 1H), 3.80 (s, 3H), 2.88e2.63 (m,
126.3, 125.3, 125.0, 108.7; HRMS: calcd for
C
16H10O3
2H), 2.49 (dd, J¼19.2, 8.4 Hz, 1H), 2.40e2.28 (m, 1H), 2.27e2.18 (m,
1H), 2.18e2.08 (m, 1H), 2.07e1.98 (m, 1H), 1.95 (dd, J¼12.8, 6.0 Hz,
1H), 1.86 (dt, J¼13.3, 3.2 Hz, 1H), 1.69e1.45 (m, 4H), 1.24 (ddd,
J¼25.7, 13.2, 3.7 Hz, 1H), 1.15 (ddd, J¼24.6, 12.2, 5.0 Hz, 1H), 0.92 (s,
[MþNa]þ¼273.0522 m/z, found¼273.0527 m/z.
4.2.39. Compound 5h. Synthesized according to the general pro-
cedure C: 112.0 mg, 46% yield, orange solid; 109.5 mg recovery of
4h, 96% yield brsm. Rf¼(ethyl acetate/hexane 1:2): 0.40; IR (neat)
3H); 13C NMR (126 MHz, CDCl3)
d 220.0, 187.7, 182.3, 157.9, 145.4,
141.2, 108.0, 56.1, 49.7, 48.3, 43.6, 38.5, 35.6, 32.0, 25.8, 23.9, 23.6,
21.5, 14.2; HRMS: calcd for C19H22O4 [MþH]þ¼315.1591 m/z,
found¼315.1582 m/z.
n
¼3383, 3060, 2974, 1638, 1595, 1494, 1401, 1292, 1205, 1138 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.30 (t, J¼7.6 Hz, 2H), 7.26e7.14 (m, 3H),
6.98 (br s, 1H), 6.84 (s, 1H), 5.94 (s, 1H), 1.62 (s, 6H); 13C NMR
(75 MHz, CDCl3) 186.7, 184.4, 158.6, 153.5, 147.1, 128.4, 127.8, 126.1,
d
4.2.46. Compound 5k. A flame-dried, 5 mL microwave vial equip-
ped with a Teflon-coated stir bar and a rubber septum was charged
with compound 1j (0.2 mmol, 110.5 mg) and purged with N2 for
5 min, before the addition of THF (1 mL). The mixture was then
cooled to 0 ꢁC in ice/water bath, at which temperature H2SO4 (2:1
volume mixture of concentrated H2SO4 with water, 0.5 mL) was
added dropwise over a period of 5 min. The reaction mixture was
then warm to room temperature and stirred for 1 h, before
quenching by the addition of water (20 mL). The mixture was
extractedwith CH2Cl2 (3ꢂ20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
125.3, 109.7, 42.5, 29.2; HRMS: calcd for
C15H14O3
[MþNa]þ¼265.0835 m/z, found¼265.0835 m/z.
4.2.40. Compound 5i. Synthesized according to the general pro-
cedure C: 94.6 mg, 42% yield, yellow solid; 84.5 mg recovery of 4i,
75% yield brsm. Rf¼(ethyl acetate/hexane 1:2): 0.15; IR (neat)
n
¼3205, 3057, 2985, 2952, 1707, 1653, 1639, 1612, 1468, 1431, 1394,
1366, 1349, 1281, 1219, 1191, 1153, 1143 cmꢀ1
CDCl3) 7.22 (br s, 1H), 6.67 (s, 1H), 6.09 (s, 1H), 3.65 (s, 3H), 1.44 (s,
6H); 13C NMR (126 MHz, CDCl3)
186.7, 183.8, 175.5, 155.1, 154.4,
;
1H NMR (500 MHz,
d
d
Please cite this article in press as: Huang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.095

Z. Huang et al. / Tetrahedron xxx (2015) 1e15
13
reaction mixture was purified on silica gel column chromatography
using 50e100% EtOAc/hexanes as eluant to produce 29.7 mg, 49%
yield of compound 5k as a yellow solid. Rf¼(ethyl acetate): 0.29; IR
16.12, 25.1, 18.7; HRMS: calcd for C16H22O4 [MþNa]þ¼301.1410 m/z,
found¼301.1407 m/z.
(neat)
n
¼3241, 2930, 1730, 1655, 1627, 1597, 1456, 1401, 1363, 1321,
4.2.49. Compound 4i. A flame-dried, 100 mL round-bottom flask
equipped with a Teflon-coated stir bar and a rubber septum was
charged with compound S2 (5 mmol, 1.39 g, 1 equiv) and added
methanol and water (9:1 by volume, 50 mL). Oxalic acid (10 mmol,
900.4 mg, 2 equiv) was then added as solid. After stirring for 12 h,
the mixture was concentrated in vacuo, diluted with ethyl acetate
(100 mL), and washed with saturated sodium bicarbonate solution
(100 mL). The aqueous layer was separated and extracted with
ethyl acetate (3ꢂ100 mL), and the combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was then purified on silica gel using 20% ethyl acetate in
hexanes as eluant to afford 4i (951.7 mg, 98% yield) as a white solid.
1300, 1281, 1215, 1112 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 6.99 (br s,
1H), 6.01 (s, 1H), 2.95e2.60 (m, 2H), 2.51 (dd, J¼19.2, 8.3 Hz, 1H),
2.44e2.33 (m, 1H), 2.31e2.21 (m, 1H), 2.20e2.10 (m, 1H), 2.07e2.00
(m, 1H), 1.97 (dd, J¼12.9, 6.1 Hz, 1H), 1.88 (dt, J¼13.4, 3.3 Hz, 1H),
1.70e1.49 (m, 4H), 1.32e1.14 (m, 2H), 0.93 (s, 3H); 13C NMR
(126 MHz, CDCl3) d 220.0,188.0,183.9,153.5,147.7,139.3,108.6, 49.7,
48.3, 43.9, 38.5, 35.6, 32.1, 26.0, 23.6, 23.5, 21.5,14.2; HRMS: calcd for
C
18H20O4 [MþH]þ¼301.1417 m/z, found¼301.1417 m/z.
4.2.47. Methyl
2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)
acetate. A flame-dried, 500 mL round-bottom flask equipped with
a Teflon-coated stir bar and a rubber septum was charged with
pyridinium p-toluenesulfonate (PPTs) (25 mmol, 6.28 g, 5 mol %)
and methyl 2-(4-hydroxyphenyl)acetate (500 mmol, 83.08 g,
1.0 equiv) and then purged with a steady stream of N2 for 5 min,
prior to the addition of dry and degassed CH2Cl2 (250 mL). 3,4-
Dihydro-2H-pyran (DHP) (600 mmol, 54.74 mL, 1.2 equiv) was
then added via syringe. The mixture was stirred at room temper-
ature for 3 h, and then quenched with water (100 mL). The aqueous
layer was washed with CH2Cl2 (3ꢂ200 mL), and the combined or-
ganic layers were dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified on silica gel using 10% ethyl
acetate in hexanes as eluant to afford S1 (124.10 g, 99% yield) as
1H NMR (500 MHz, CDCl3)
2H), 3.68 (s, 3H), 1.58 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
7.22 (d, J¼8.7 Hz, 2H), 6.80 (d, J¼8.8 Hz,
d
178.0,
154.5, 136.5, 126.9, 115.2, 52.3, 45.8, 26.6. The characterization data
match the previous report.30
4.2.50. Compound 4f. A flame-dried, 100 mL Radley tube equipped
with a Teflon-coated stir bar and a rubber septum was charged with
4-bromophenol (5 mmol, 865.0 mg, 1.0 equiv), Pd(PPh3)2Cl2
(0.1 mmol, 70.19 mg, 2 mol %), PPh3 (0.2 mmol, 52.46 mg, 4 mol %),
2-methoxyphenylboronic acid (911.8 mg, 6.0 mmol), and K2CO3
(25 mmol, 3.46 g, 5 equiv) and then purged with a steady stream of
N2 for 5 min, prior to the addition of degassed DMF and water
(50 mL, 5:1 mixture by volume). The reaction mixture was then
stirred under N2 at 80 ꢁC for 12 h, cooled to room temperature, and
diluted with water (50 mL). The mixture was extracted with EtOAc
(3ꢂ50 mL). The combined organic layer was washed with water
(100 mL) and brine (100 mL). It was dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was then purified on
silica gel using 10e20% ethyl acetate in hexanes as eluant to afford
4f (825.9 mg, 82% yield) as a white solid. 1H NMR (500 MHz, CDCl3)
a colorless oil. Rf¼(EtOAc/hexane 1:9): 0.30; IR (neat)
1509, 1453, 1355, 1231, 1109, 1036, 919 cmꢀ1 1H NMR (300 MHz,
acetone-d6)
n
¼2943, 1613,
;
d
7.20 (d, J¼8.6 Hz, 2H), 7.00 (d, J¼8.6 Hz, 2H), 5.42 (t,
J¼3.3 Hz,1H), 3.84 (ddd, J¼12.0, 9.2, 3.2 Hz,1H), 3.63 (s, 3H), 3.57 (s,
2H), 3.55 (ddd, J¼¼12.0, 9.2, 3.2 Hz, 1H), 2.03e1.90 (m, 1H),
1.90e1.74 (m, 2H), 1.73e1.49 (m, 3H); 13C NMR (75 MHz, acetone-
d6)
d 171.6, 156.2, 130.1, 127.5, 116.4, 96.2, 61.5, 51.1, 39.6, 30.2, 25.1,
18.7; HRMS: calcd for
C
14H18O4 [MþNa]þ¼273.1097 m/z,
found¼273.1106 m/z. This compound was reported previously.29
However, we were not able to find the characterization data.
d
7.46 (d, J¼8.7 Hz, 2H), 7.36e7.30 (m, 2H), 7.05 (td, J¼7.5, 1.0 Hz,
1H), 7.01 (d, J¼8.8 Hz, 1H), 6.90 (d, J¼8.7 Hz, 2H), 4.85 (br s, 1H),
3.84 (s, 3H); 13C NMR (126 MHz, CDCl3)
156.4, 154.6, 131.1, 130.8,
d
4.2.48. Methyl 2-methyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phe-
nyl)propanoate. A flame-dried, 500 mL round-bottom flask equip-
ped with a Teflon-coated stir bar and a rubber septum was charged
with potassium tert-butoxide (tBuOK) (150 mmol, 16.83 g,
3.0 equiv) and then purged with a steady stream of N2 for 5 min,
prior to the addition of dry and degassed THF (200 mL). In a sepa-
rate, flame-dried, 100 mL round-bottom flask equipped with a Tef-
lon-coated stir bar and a rubber septum was charged with
compound S1 (50 mmol, 12.51 g, 1.0 equiv) and then purged with
a steady stream of N2 for 5 min, prior to the addition of dry and
degassed THF (50 mL) to afford a homogeneous solution. It was
130.7, 130.3, 128.2, 120.9, 115.0, 111.2, 55.6. The characterization
data match the previous report.21
4.2.51. Compound 4g. A flame-dried, 100 mL Radley tube equipped
with a Teflon-coated stir bar and a rubber septum was charged with
4-bromophenol (5 mmol, 865.0 mg, 1.0 equiv), Pd(PPh3)2Cl2
(0.1 mmol, 70.19 mg, 2 mol %), PPh3 (0.2 mmol, 52.46 mg, 4 mol %),
naphthalen-1-ylboronic acid (1.03 g, 6.0 mmol), and K2CO3
(25 mmol, 3.46 g, 5 equiv) and then purged with a steady stream of
N2 for 5 min, prior to the addition of degassed DMF and water
(50 mL, 5:1 mixture by volume). The reaction mixture was then
stirred under N2 at 80 ꢁC for 12 h, cooled to room temperature and
diluted with water (50 mL). The mixture was extracted with EtOAc
(3ꢂ50 mL). The combined organic layer was washed with water
(100 mL) and brine (100 mL). It was dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was then purified on
silica gel using 10e20% ethyl acetate in hexanes as eluant to afford
4g (728.7 mg, 3.31 mmol, 66% yield) as a white solid. 1H NMR
t
added to the BuOK solution in THF via syringe at ꢀ78 ꢁC. After
stirring for 20 min at ꢀ78 ꢁC, iodomethane (125 mmol, 7.78 mL,
2.5 equiv) was added via syringe dropwise to the solution, and the
resulting mixture was stirred at ꢀ78 ꢁC for 1 h and then warmed to
room temperature and stirred for another 30 min before quenching
with water (100 mL). It was extracted with ethyl acetate
(3ꢂ100 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified on silica gel using 5% ethyl acetate in hexanes as eluant to
afford S2 (12.03 g, 86% yield) as a pale-yellow oil. Rf¼(EtOAc/hexane
(500 MHz, CDCl3)
d
7.97 (d, J¼8.5 Hz,1H), 7.95 (d, J¼8.0 Hz, 1H), 7.89
(d, J¼8.2 Hz, 1H), 7.58e7.51 (m, 2H), 7.48 (ddd, J¼8.3, 6.8, 1.4 Hz,
1H), 7.45 (dd, J¼7.1, 1.2 Hz, 1H), 7.42 (d, J¼8.6 Hz, 2H), 7.01 (d,
1:9): 0.40; IR (neat)
1436, 1399, 1215, 1121, 1016, 937, 808, 647, 468 cmꢀ1
(300 MHz, acetone-d6)
2H), 5.42 (t, J¼3.3 Hz, 1H), 3.84 (ddd, J¼11.3, 9.2, 3.4 Hz, 1H), 3.60 (s,
3H), 3.54 (ddd, J¼11.3, 9.2, 3.4 Hz, 1H), 2.02e1.89 (m, 1H), 1.89e1.74
(m, 2H), 1.72e1.55 (m, 3H), 1.52 (s, 6H); 13C NMR (75 MHz, acetone-
n
¼3376, 2068, 3013, 2974, 2925, 2848, 1600,
J¼8.6 Hz, 2H), 5.24 (br s, 1H); 13C NMR (126 MHz, CDCl3)
d 154.9,
;
1H NMR
139.8, 133.9, 133.4, 131.8, 131.4, 128.3, 127.4, 126.9, 126.1, 126.0,
125.8, 125.4, 115.2. The characterization data match the previous
report.31
d
7.25 (d, J¼8.8 Hz, 2H), 6.99 (d, J¼8.8 Hz,
4.2.52. Compound 1a. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel. 7.21 g, 92%
d6) d 176.4, 155.9,137.8, 126.5,116.2, 96.1, 61.5, 51.3, 45.6, 30.2, 26.15,
Please cite this article in press as: Huang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.095

14
Z. Huang et al. / Tetrahedron xxx (2015) 1e15
yield, red solid. 1H NMR (500 MHz, CDCl3)
d
7.40 (d, J¼8.7 Hz, 2H),
33% yield, red solid. 1H NMR (500 MHz, CDCl3)
d
7.52 (t, J¼8.0 Hz,
6.96 (d, J¼8.7 Hz, 2H), 6.27 (s, 1H), 5.44 (s, 1H), 1.37 (s, 9H), 1.26 (s,
4H), 7.37 (t, J¼7.5 Hz, 2H), 7.23 (d, J¼7.6 Hz, 4H), 5.59 (s, 2H). The
9H). The characterization data match the previous report.21
characterization data match the previous report.21
4.2.53. Compound 1b. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel. 4.37 g,
Acknowledgements
100% yield, red solid. 1H NMR (500 MHz, CDCl3)
d 7.39e7.31 (m, 4H),
The authors are grateful for financial support provided by the
Natural Sciences and Engineering Research Council of Canada
(Discovery Grant to J.-P.L.), the Fonds de Recherche du
7.31e7.23 (m, 3H), 7.23e7.17 (m, 3H), 7.15 (d, J¼8.8 Hz, 2H), 6.67 (s,
1H), 6.33 (d, J¼8.8 Hz, 2H), 5.48 (s, 1H), 1.76 (s, 6H), 1.65 (s, 6H). The
characterization data match the previous report.21
ꢀ
QuebecdNature et Technologies (Team Grant to J.-P.L), McGill
University-Canadian Institutes of Health Drug Development
Trainee Program (doctoral fellowship to K.V.N.E.), the NSERC-Create
Program in Green Chemistry and Catalysis (graduate fellowship to
Z.H. and undergraduate fellowship to O.K.), the FQRNT Center in
Green Chemistry and Catalysis, and McGill University (start-up
funds to J.P.L.).
4.2.54. Compound 1c. Synthesized according to the general pro-
cedure D. Purified with 30% EtOAc/hexanes on silica gel. 902.4 mg,
90% yield, red solid. Rf¼(ethyl acetate/hexane 1:2): 0.39; IR (neat)
n
¼1722, 1652, 1572, 1502, 1365, 1255, 1219, 1168, 1146 cmꢀ1
;
1H
NMR (500 MHz, CDCl3)
d
7.40 (d, J¼8.8 Hz, 2H), 6.95 (d, J¼8.8 Hz,
2H), 6.42 (s, 1H), 5.52 (s, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 1.58 (s, 6H),
1.57 (s, 6H); 13C NMR (126 MHz, CDCl3)
d
180.4, 178.4, 176.6, 175.0,
Supplementary data
168.4, 153.8, 150.3, 143.8, 127.9, 126.0, 120.5, 106.9, 52.6, 52.4, 46.2,
45.5, 26.6, 25.3; HRMS: calcd for C22H24O7 [MþNa]þ¼423.1414 m/z,
found¼423.1422 m/z.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.04.095.
4.2.55. Compound 1d. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel. 997.5 mg,
57% yield, red solid. Rf¼(ethyl acetate/hexane 1:4): 0.37; IR (neat)
References and notes
1. (a) The Chemistry of the Quinonoid Compounds; Wiley: New York, NY, 1988, Vols.
1e2; (b) Fishwick, C. W. G.; Jones, D. W. ortho-Quinonoid compounds In The
Quinonoid Compounds (1988); John Wiley & Sons, Inc.: New York, NY, 2010;
pp 403e453.
2. (a) Riley, P. A.; Ramsden, C. A.; Land, E. J. Biological Chemistry of o-Quinones In
Melanins and Melanosomes: Biosynthesis, Structure, Physiological and Pathologi-
n
¼3058, 1642, 1550, 1512, 1483, 1370, 1253, 1217, 1158 cmꢀ1
;
1H
NMR (500 MHz, CDCl3)
d
7.68 (d, J¼8.6 Hz, 2H), 7.63 (dd, J¼7.7,
1.8 Hz, 2H), 7.59 (d, J¼7.1 Hz, 2H), 7.55e7.47 (m, 5H), 7.41 (t,
J¼7.3 Hz, 1H), 7.19 (d, J¼8.6 Hz, 2H), 6.54 (s, 1H), 5.75 (s, 1H); 13C
ꢀ
cal Functions; Borovansky, J., Riley, P. A., Eds.; Wiley-VCH: Weinheim, Germany,
NMR (126 MHz, CDCl3) d 179.9,178.8,168.2,151.6,150.1,140.3,139.7,
ꢀ_
2011; pp 63e86; (b) Rozanowska, M. Properties and Functions of Ocular Mel-
anins and Melanosomes In Melanins and Melanosomes; Wiley-VCH Verlag
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kamatsu, K.; d’ischia, M.; Napolitano, A.; Pezzella, A. Structure of Melanins In
Melanins and Melanosomes; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2011; pp 167e185; (d) García-Borron, J. C.; Olivares Sanchez, M. C.
Biosynthesis of Melanins In Melanins and Melanosomes; Wiley-VCH Verlag
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man, J. P. Quinone Cofactors In eLS; John Wiley & Sons: 2001.
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133.5, 130.4, 129.2, 129.09, 129.06, 129.0, 128.5, 127.8, 127.1, 121.3,
106.9; HRMS: calcd for
C
24H16O3 [MþNa]þ¼375.0992 m/z,
found¼375.1000 m/z.
ꢀ
ꢀ
4.2.56. Compound 1e. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel. 2.77 g, 97%
yield, red solid. 1H NMR (500 MHz, CDCl3)
d
7.30 (d, J¼8.4 Hz, 2H),
6.99 (d, J¼8.6 Hz, 2H), 6.31 (d, J¼1.1 Hz, 1H), 5.49 (s, 1H), 3.22
(heptd, J¼6.8,1.1 Hz,1H), 2.94 (hept, J¼6.9 Hz,1H),1.30 (d, J¼6.8 Hz,
6H), 1.26 (d, J¼6.9 Hz, 6H). The characterization data match the
previous report.21
4.2.57. Compound 1f. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel. 3.55 g, 97%
yield, red solid. 1H NMR (500 MHz, CDCl3)
d
7.29 (d, J¼8.5 Hz, 2H),
7.00 (d, J¼8.6 Hz, 2H), 6.29 (d, J¼0.9 Hz, 1H), 5.49 (s, 1H), 2.84 (tdd,
J¼11.5, 2.4, 1.9 Hz, 1H), 2.55 (tt, J¼11.3, 2.8 Hz, 1H), 2.03 (d,
J¼11.9 Hz, 2H), 1.96e1.83 (m, 6H), 1.82e1.73 (m, 2H), 1.49e1.36 (m,
6H), 1.36e1.19 (m, 4H). The characterization data match the pre-
vious report.21
10. Shaik, F. H.; Kar, G. K. Beilstein J. Org. Chem. 2009, 5, 47.
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4.2.58. Compound 1g. Synthesized according to the general pro-
cedure D. Purified with 20% EtOAc/hexanes on silica gel: 797.1 mg,
52% yield, red solid. 1H NMR (500 MHz, CDCl3)
1H), 6.79e6.74 (m, 2H), 5.41 (s, 1H), 2.82e2.70 (m, 4H), 2.70e2.62
(m, 2H), 2.49e2.39 (m, 2H), 1.86e1.76 (m, 6H), 1.76e1.68 (m, 2H).
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d
7.10 (d, J¼7.9 Hz,
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cedure D. Purified with 40% EtOAc/hexanes on silica gel. 1.43 g, 55%
yield, red solid. 1H NMR (500 MHz, CDCl3)
d
7.04 (d, J¼9.1 Hz, 2H),
6.97 (d, J¼9.1 Hz, 2H), 5.85 (s, 1H), 5.51 (s, 1H), 4.00 (s, 3H), 3.85 (s,
3H). The characterization data match the previous report.21
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cedure D. Purified with 20% EtOAc/hexanes on silica gel. 933.9 mg,
Please cite this article in press as: Huang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.095

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Please cite this article in press as: Huang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.095